Micelles are a class of surfactants that form organized structures, referred to as colloidal spheres, in aqueous media. The hydrophobic shell of micelles makes the entire assembly water-soluble while the lipophilic core solubilizes hydrophobic molecules. Attempts have been made to use micelles in drug delivery applications because the lipophilic core serves as a microcontainer for drugs, thereby segregating the drugs from the outer environment by the hydrophilic segments. Micelles or colloids encapsulate the drug, shielding the body from potentially toxic levels of drug while simultaneously protecting the drug from inactivating agents in the blood and lymphatic system. Thus, solubilization of water-insoluble drugs by micelles has long been investigated as a means for improving solubility for drug delivery, in particular for parenteral or oral administration, and also for ophthalmic, topical, rectal and nasal delivery (Florence, A. Techniques of Solubilization of Drugs, Ed. Yalkowsky, S. (New York: Marcel Dekker, 1981); Atwood, D. and Florence, A. T. Pharmaceutical Aspects of Solubilization, Surfactant Systems. Their Chemistry, Pharmacy and Biology, (London: Chapman Hall, 1983):293-387).
However, the formation of micelles is both temperature- and concentration-dependent. The concentration dependency is defined as the critical micelle concentration or CMC. Thus, after micelles are injected into the bloodstream, they begin to equilibrate between the micellar, colloidal structure and individual surfactant molecules. Because of the change in micellar structure and size, control over the release of drugs within the micellar microcontainer cannot be maintained for long periods. Typically drug is released over a period of hours and this release is often inconsistent over this period. Thus, the thermodynamic equilibrium between surfactant and micelles may ultimately cause serious toxicity problems due to potentially large fluctuations in drug concentrations accompanied by the breakdown in micellar structure into surfactant molecules. This dilution is particularly large after oral and intravenous administration and can cause unwanted precipitation of hydrophobic drugs.
Thus, while micelles are frequently evaluated for use as drug delivery systems, there are only a few products on the market that are considered practical. This is due to the eventual aggregation and/or precipitation of drugs resulting from equilibration of micelles back to the monomer and the solubilization capacity being too low to be of practical use.
Attempts have been made to design non-ionic surfactants such as poly(ethylene oxide) containing molecules with improved solubilization characteristics. An early approach involved the production of large micellar systems. However, despite the increased micelle size, solubilization decreased with the longer hydrophobic chains. This decrease was attributed to deleterious changes in the poly(ethylene oxide) chains nearest to the core, the main locus of solubilization for most drugs (Elworthy, P. and Patel, M. J. Pharm. Pharmacol. 1982 34:543).
Liu et al. (Polym. Preprint., 1997 38(2):582-583) report the synthesis of a single species of hyperbranched polymeric micelles for encapsulation of small hydrophobic organic molecules. This species contains no divalent amino acid moiety. Instead, this species comprises a 1,1,1-tris(hydroxyphenyl)ethane moiety and an acylated mucic acid moiety as the divalent dicarboxylic moiety. There remains a need for suitable delivery systems for the administration of hydrophobic molecules.